IL-9 和 Blimp-1 保护 2 组先天性淋巴样细胞在过敏性哮喘中的转录特性
2026/04/28
摘要
过敏性哮喘由 2 型免疫反应驱动，其中包括 2 型先天性淋巴样细胞（ILC2s）。尽管 ILC2s 会被组织警报素白细胞介素（IL）-33 和 IL-25 激活，但这些信号本身并不能强制维持 2 型特性，且维持 2 型细胞因子表达的机制尚不清楚。在此，我们展示了过敏原诱导的 IL-33 和 IL-25 会迅速诱导 IL-9 的产生，IL-9 进而使 ILC2s 中的转录抑制因子 Blimp-1 上调。Blimp-1 通过直接抑制 1 型炎症程序（包括干扰素－γ和肿瘤坏死因子的表达）来维持 2 型免疫。在 ILC2s 中敲除 Blimp-1 会增加 1 型细胞因子的产生，并减少肺部的 IL-5 和 IL-13 表达、嗜酸性粒细胞募集以及粘液产生。相比之下，在缺乏 Blimp-1 的情况下 IL-9 表达增强，导致肥大细胞募集增加。综上所述，这些发现确定了 Blimp-1 是 ILC2 转录忠实度的关键调节因子，它在过敏反应期间既能稳定 2 型炎症，又能限制发散的炎症程序。
IL-9 and Blimp-1 protect the transcriptional identity of group 2 innate lymphocytes in allergic asthma
Yibo Zheng, Shilpi Giri, Jinyi Zhang, Yijia Chen, Aaron Yang, Sagar L Kale, Harshita Beeravolu, Abbe Pannucci, Anthony D Marinov, Jeremy S Tilstra, Kun He, Arianna Creech, Daniella M Schwartz, Rachel A Gottschalk, Nicolas Bouladoux, Yasmine Belkaid, Anthony R Cillo, Anuradha Ray, Amanda C Poholek
Abstract
Allergic asthma is driven by type 2 immune responses, including type 2 innate lymphoid cells (ILC2s). Although ILC2s are activated by the tissue alarmins interleukin (IL)-33 and IL-25, these signals do not intrinsically enforce type 2 identity and the mechanisms that maintain type 2 cytokine expression remain unclear. Here we show that allergen-induced IL-33 and IL-25 rapidly induce IL-9, which in turn upregulates the transcriptional repressor Blimp-1 in ILC2s. Blimp-1 sustains type 2 immunity by directly repressing type 1 inflammatory programs, including expression of interferon-γ and tumor necrosis factor. Deletion of Blimp-1 in ILC2s increased type 1 cytokine production and reduced IL-5 and IL-13 expression, eosinophil recruitment and mucus production in the lung. In contrast, IL-9 expression was enhanced in the absence of Blimp-1, leading to increased mast cell recruitment. Together, these findings identify Blimp-1 as a key regulator of ILC2 transcriptional fidelity that stabilizes type 2 inflammation while constraining divergent inflammatory programs during allergic responses.
过敏性哮喘由 2 型免疫反应驱动，其中包括 2 型先天性淋巴样细胞（ILC2s）。尽管 ILC2s 会被组织警报素白细胞介素（IL）-33 和 IL-25 激活，但这些信号本身并不能强制维持 2 型特性，且维持 2 型细胞因子表达的机制尚不清楚。在此，我们展示了过敏原诱导的 IL-33 和 IL-25 会迅速诱导 IL-9 的产生，IL-9 进而使 ILC2s 中的转录抑制因子 Blimp-1 上调。Blimp-1 通过直接抑制 1 型炎症程序（包括干扰素－γ和肿瘤坏死因子的表达）来维持 2 型免疫。在 ILC2s 中敲除 Blimp-1 会增加 1 型细胞因子的产生，并减少肺部的 IL-5 和 IL-13 表达、嗜酸性粒细胞募集以及粘液产生。相比之下，在缺乏 Blimp-1 的情况下 IL-9 表达增强，导致肥大细胞募集增加。综上所述，这些发现确定了 Blimp-1 是 ILC2 转录忠实度的关键调节因子，它在过敏反应期间既能稳定 2 型炎症，又能限制发散的炎症程序。
（北京朝阳医院呼吸与危重症医学科 顾宪民 摘译 中日友好医院呼吸与危重症医学科 林江涛 审校）
（Nat Immunol. 2026 Apr 24. doi: 10.1038/s41590-026-02509-3. ）
（Nat Immunol. 2026 Apr 24. doi: 10.1038/s41590-026-02509-3. ）
IL-9 and Blimp-1 protect the transcriptional identity of group 2 innate lymphocytes in allergic asthma
Yibo Zheng, Shilpi Giri, Jinyi Zhang, Yijia Chen, Aaron Yang, Sagar L Kale, Harshita Beeravolu, Abbe Pannucci, Anthony D Marinov, Jeremy S Tilstra, Kun He, Arianna Creech, Daniella M Schwartz, Rachel A Gottschalk, Nicolas Bouladoux, Yasmine Belkaid, Anthony R Cillo, Anuradha Ray, Amanda C Poholek
Abstract
Allergic asthma is driven by type 2 immune responses, including type 2 innate lymphoid cells (ILC2s). Although ILC2s are activated by the tissue alarmins interleukin (IL)-33 and IL-25, these signals do not intrinsically enforce type 2 identity and the mechanisms that maintain type 2 cytokine expression remain unclear. Here we show that allergen-induced IL-33 and IL-25 rapidly induce IL-9, which in turn upregulates the transcriptional repressor Blimp-1 in ILC2s. Blimp-1 sustains type 2 immunity by directly repressing type 1 inflammatory programs, including expression of interferon-γ and tumor necrosis factor. Deletion of Blimp-1 in ILC2s increased type 1 cytokine production and reduced IL-5 and IL-13 expression, eosinophil recruitment and mucus production in the lung. In contrast, IL-9 expression was enhanced in the absence of Blimp-1, leading to increased mast cell recruitment. Together, these findings identify Blimp-1 as a key regulator of ILC2 transcriptional fidelity that stabilizes type 2 inflammation while constraining divergent inflammatory programs during allergic responses.
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